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Circulating Progenitor Cells and Cardiovascular Disease

Circulating Progenitor Cells and Cardiovascular Disease. Arshed A. Quyyumi, MD Professor of Medicine Emory Clinical Cardiovascular Research Institute (ECCRI) Emory University School of Medicine Atlanta, GA. Circulating Progenitor Cells and Cardiovascular Disease. Grant support:

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Circulating Progenitor Cells and Cardiovascular Disease

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  1. Circulating Progenitor Cells and Cardiovascular Disease Arshed A. Quyyumi, MD Professor of Medicine Emory Clinical Cardiovascular Research Institute (ECCRI) Emory University School of Medicine Atlanta, GA

  2. Circulating Progenitor Cells and Cardiovascular Disease Grant support: National Institutes of Health, American Heart Association, Woodruff Fund, Emory Heart and Vascular Center, Sanofi Aventis, Novartis, Lilly, Pfizer, Forest, Amgen, Genzyme Advisory Boards: Amorcyte/Neostem, Genway/Firstmark Soteria Stemedica

  3. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and gender • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  4. Endothelial Progenitor Cells Blood cells Hematopoeitic cells Stromal or Mesenchymal MAPC Osteocytes, Chondrocytes Myocytes (Skeletal) (Cardiac) Adult Bone Marrow Stem Cell Plasticity Neural cells Epidermal cells Ectodermal Progenitor Cells Mesodermal Progenitor Cells Bone Marrow Stem Cells Endodermal Progenitor Cells Hepatocytes Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.

  5. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and gender • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  6. Flow Cytometry Gated on CD34+ within MNCs Within CD34+ gate, 4 quadrants for marker CD133 and VEGF-2R Gated on MNCs CD45med

  7. Fluorescent activated cell sorting (FACS) analysis for bone marrow derived progenitor cell populations • CD34: Hematopoietic stem cell • CD133: Immature progenitors • CD133+/VEGF2R+: Differentiates between immature and mature endothelial PCs • CD34+/CD133+/VEGF2R+: Presumed ‘EPC’ enriched • CXCR4: Epitope that is associated with homing to areas of ischemia that express SDF-1 Peichev M et al Blood 2000; 95:952 Hirschi KK. et al ATVB 2008;28:1584

  8. Cell Type: Isolated CD34⁺CellsMostAble to Improve Perfusion, Prevent Apoptosis and Rescue Hibernating Cardiomyocytes CD34⁺ Cells Exhibit Increased Potency and Safety for Therapeutic Neovascularization after AMI Compared with Total Mononuclear Cells in Nude Rats: PBS = Phosphate-buffered saline loMNCs = 5x10^5 MNC hiMNCs = contains 5x10^5 CD34+ cells within MNCs CD34+ = 5x10^5 CD34+ cells Capillary Density (perfusion) is greatest in CD34+ cell cohort, and this correlates with decreased incidence of fibrosis. Effect increases with dose. Kawamoto et al., Circulation 2006;114;2163-2169 13

  9. Endothelial progenitor cell therapy for acute myocardial infarction • Cell types: bone marrow mononuclear cells, CD34+, etc. • CD34+ cells constitute 0.1 to 0.2% of bone marrow mononuclear cells BM mononuclear cells • FDG labeled bone marrow mononuclear cells and injected intracoronary in post MI patients • Uptake of BM mononuclear cells: 1.3 to 2.6% in MI region • Uptake of CD34+ cells: 14-39% in MI region CD34+ cells Hofmann et al Circ 2005;111:2198-2202

  10. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and gender • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  11. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  12. Circulating progenitor cells in acute coronary syndromes: comparison with stable CAD • 90 ACS patients (mean age 65±15 yrs, 73% male, 10% STEMI, 76% NSTEMI, and 13% unstable angina) • Blood samples were obtained at the time of cardiac catheterization for enumeration of CPCs as CD45dim cells using flow cytometry. • An age- and gender-matched (1:2) cohort of stable CAD patients were randomly selected as a control group

  13. Comparison of VEGF2R-expressing CPCs between stable CAD and ACS categories * * * * * CD34+/VEGF2R+ in CD45dim (cells/µL) UA NSTEMI STEMI Stable CAD UA NSTEMI STEMI Stable CAD *P<0.05 when compared to stable CAD

  14. Mental Stress • Standardized public speaking task • Role playing a difficult interpersonal situation where a close relative in a nursing home is being mistreated. • Hemodynamic and electrocardiographic monitoring Mental Stress Physical Stress Rest Rest Mental stress Physical stress

  15. Results • Effect of mental stress on acute mobilization of progenitor cells • MS challenge provoked an average 21% increase in the number of circulating CD34+/VEGF2R+/CXCR4+ cells

  16. Relationship between progenitor cells and ischemia during mental stress • Patients with mental stress ischemia had higher circulating number of CXCR4-expressing cells at baseline

  17. Circulating Progenitor Cells and Coronary Microvascular Dysfunction: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) Study • Patients: • 160 women enrolled in the WISE-CVD Study with ischemia during stress testing • No obstructive CAD • Protocol: • CFR measured as ratio of hyperemic average peak velocity (APV) in response to intracoronary adenosine to baseline APV • Lower CFR with adenosine correlated significantly with higher levels of CD34+, CD34+/CD133+ and CD34+/CXCR4+ cells

  18. Circulating Progenitor Cells and Coronary Microvascular Dysfunction: Results from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction (WISE-CVD) Study • Patients: • 160 women enrolled in the WISE-CVD Study with ischemia during stress testing • No obstructive CAD • Protocol: • Microvascular endothelial function measured as the CBF response to intracoronary acetylcholine (n=48) • Lower CBF with acetylcholine correlated significantly with higher CD34+/CXCR4+ and CD34+/VEGF+.

  19. Progenitor Cells and ischemic syndromes • ACS is associated with mobilization of VEGF2R and CXCR4 expressing PCs • Subjects with microvascular coronary ischemia with reduced flow reserve and endothelial dysfunction have higher circulating PC subsets • PC expressing CXCR4, denoting cells with a capacity to home to areas of ischemia, are increased in those who develop ischemia during MS. • This suggests that even mild ischemia during daily living may stimulate PC mobilization.

  20. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and sub-clinical vascular disease • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  21. Risk factors, Vascular Injury, and Regenerative Capacity Risk Factors Progenitor Cells Endothelial injury Endothelial dysfunction, Arterial stiffness Vascular Repair Atherogenesis

  22. Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) • Patients undergoing coronary angiography: Treated with guideline based therapies • 502 patients in a Discovery cohort ; • 403 patients in a Validation cohort. • Total Pooled 905; age 63yrs; 65% male • PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, CD133, VEGFR2 and/or CXCR4 • Followed patients in each cohort for a mean of 2.7 & 1.2 years, for the primary endpoint of death or myocardial infarction (MI). • 92 death/MI (10%) • Higher counts of CD34+ and CD34+/CD133+ cells correlated with: • younger age (p<0.001 both), • male gender (p=0.04 and p<0.011) • higher GFR (p<0.001 both) • Higher CD34+/CD133+ also with greater BMI (p<0.001).

  23. Relationship Between circulating Progenitor Cell Counts and Event Free Survival (Major Events - Death/MI) CD34+ C statistic improved from 0.713 to 0.752, p=0.024 for CD34/133+

  24. Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) • Patients undergoing coronary angiography • 502 patients in a Discovery cohort ; • 403 patients in a Validation cohort. • Total Pooled 905; age 63yrs; 65% male • PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, CD133, VEGFR2 and/or CXCR4 • Followed patients in each cohort for a mean of 2.7 & 1.2 years, for the primary endpoint of death or myocardial infarction (MI). • 92 death/MI

  25. Relationship Between circulating Progenitor Cell Counts and Event Free Survival (Major Events - Death/MI)

  26. Relationship Between circulating Progenitor Cell Counts and Long term CVD outcomes (Death/MI) Conclusion: Low levels of circulating PCs, defined as co-expression of CD34 and CD133 and CXCR4 epitopes are robustly associated with risk of future death/MI in patients with CAD. Implications; CD34+/CD133+ cells that are enriched for bone marrow-derived hematopoietic and endothelial progenitors, may represent an index of global regenerative potential PCs protect or regenerate damaged endothelium by local or systemic paracrine effects, The predictive value of PCs as risk markers was equal or greater than conventional risk factors such as smoking.

  27. Circulating Progenitor Cells and Cardiovascular Disease • Circulating progenitor cells • CD34+ cell populations • Circulating progenitor cells and gender • Circulating progenitor cells and ischemic syndromes • Circulating progenitor cells and CVD outcomes • CD34+ cells as therapy for vascular diseases

  28. Atherosclerosis Incidence PCs Risk PCs Repair Repair Risk Age or Risk Factor Years

  29. AcknowledgementsEmory Clinical Cardiovascular Research institute • Viola Vaccarino • Emir Veledar • A Maziar Zafari • Laurence Sperling • Edmund Waller • Qunna Li • DeCode Genetics • Dean Jones PhD (Metabolomics) • Charles Searles (miRNA) • Greg Gibson PhD (Transcriptomics) • Arshed Quyyumi • Riyaz Patel • Danny Eapen • Nima Ghassemzadeh • Ronnie Ramadan • Ibhar Al Mheid • Girum Mekonnen • Joseph Poole • Robert Neuman • Pankaj Manocha • Hatem Kassem • Alanna Morris • Ayaz Rahman • Saurabh Dhawan • Salman Sher • Ying Liu • Nino Kavtaradze • Elizabeth Rocco • Sherri Mcdonald • Cath Lab Attendings and Staff • Fellows/ Research Volunteers

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